This application is for a predoctoral fellowship awarded by the National Cancer Institute to physician-scientist trainees. The applicant is a trainee of the Medical Scientist Training Program at the University of Pennsylvania Perelman School of Medicine. This award would help her achieve her career goal of becoming a physician- scientist investigating the role of chromatin in cancer. DNA double-strand breaks (DSBs) destabilize the genome. When DSBs are not properly repaired, it can lead to toxic chromosomal rearrangements and malignant transformation. DSBs are repaired by either non-homologous end joining (NHEJ) or homologous recombination (HR). The balance between these two pathways is critical for maintaining genomic integrity. HR factors, such as the BRCA1 tumor suppressor, are often lost or mutated in cancers, resulting in excessive NHEJ and erroneous end joining. Our lab has reported that at damage sites, the histone acetyltransferase TIP60 promotes HR and prevents excessive NHEJ factor accumulation. However, TIP60 acts as part of a multi-subunit complex, and other subunits, such as p400 chromatin remodeler, also help recruit BRCA1 and exclude the NHEJ factor 53BP1. This suggests that in addition to acetylation, the chromatin remodeling activity of the TIP60-p400 complex can also regulate the HR-NHEJ balance at damage sites. For Aim 1, I will test whether TIP60-p400 inhibits NHEJ by destabilizing nucleosomes near double-strand breaks. It is also not clear how this complex recognizes sites of damage. For Aim 2, I will investigate whether a candidate histone modification recruits TIP60-p400 to damage sites to promote HR. Results from these experiments will elucidate how TIP60-p400 recognizes damage and mediates HR to protect the integrity of the genome and prevent cancer.